FDA Issues New Labeling for Immediate-Release Opioids

March 23, 2016

On the heels of a new broad initiative to combat opioid abuse in the US, the FDA has made significant changes to labeling requirements for immediate-release opioids, similar to what already exists for extended-release/long-acting (ER/LA) products.

New labeling and Boxed Warning for immediate-release opioids.In another important move to reduce the misuse and abuse of opioid medication, the U.S. Food and Drug Administration announced significant relabeling requirements for the most commonly prescribed opioids—immediate-release (IR) formulas.

The new labeling will now include a new boxed warning addressing risks for misuse, abuse, addiction, overdose, and death, according to a press release from the FDA.1

The current relabeling action by the FDA is similar to the action taken by the agency in 2013 for extended release/long-acting (ER/LA) opioid analgesics.

According to Douglas Throckmorton, MD, deputy center director of regulatory programs, FDA Center for Drug Evaluation and Research, the new labeling marks a “substantial” change for these products.

“We know that there is persistent abuse, addiction, overdose mortality with IR opioid products,” said Dr. Throckmorton. “Today, we have taken an important next step in clarifying and making more prominent the known risks of IR opioid medications.”

New Indication Labeling

Traditionally, IR opioids were viewed as "weaker" opioids compared to their ER/LA counterparts. Even the World Health Organization, in its 3-Step Analgesic Ladder, refers to them as "weak" opioids. The ladder views all opioids as secondary to non-opioid measures, which includes non-opioid pharmaceuticals and non-pharmacologic measures. These current label changes should end this debate over which of today’s opioids are weak or strong.

It is well known that IR opioids are prescribed more frequently than their ER/LA counterparts, reflecting a general assumption by physicians that there are somehow safer drugs.

But in the new FDA labeling, the indications for use stated on the prescribing information have been updated to state that IR products should not be used for moderate pain symptoms. Instead, IR opioids should only be indicated for pain that is "severe enough to require them, in the instance that alternative treatments (non-opioid analgesics, appropriate opioid combination products, etc) are ineffective."

“Opioid addiction and overdose have reached epidemic levels over the past decade, and the FDA remains steadfast in our commitment to do our part to help reverse the devastating impact of the misuse and abuse of prescription opioids,” Robert Califf, MD, FDA commissioner, stated in a press release. “Today’s actions are one of the largest undertakings for informing prescribers of risks across opioid products, and one of many steps the FDA intends to take this year as part of our comprehensive action plan to reverse this epidemic.”

Additional Warnings

The boxed warning also requires a precaution that describes how chronic maternal use of opioids during a pregnancy can result in neonatal opioid withdrawal syndrome (NOWS), a potentially fatal condition a newborn may be exposed to if opioid drugs are consumed by the mother over a prolonged period while the infant is in utero.

The new IR labels include a number of updates to safety information, including more detailed dosing guidelines with clearer instructions on patient monitoring and drug administration, including initial dosage, dosage changes during therapy, and a warning to not abruptly stop treatment of opioids in a patient who has become physically dependent on them.

The FDA also is requiring an update across the board for all opioid products (ER/LA and IR) to include information on potentially harmful drug interactions that can result in serotonin syndrome, a serious, potentially fatal central nervous system complication.

The updated labeling also will address opioid effects on the endocrine system, such as adrenal insufficiency or Addison’s disease, a rare hormonal disorder that results from the adrenal glands not producing enough cortisol. The labeling also now will mention androgen deficiency, a complication that results in decreased sex hormones in the body. The labeling will make clear these complications can result regardless if the patient is taking the opioid for treating pain or as part of a medication-assisted treatment (MAT) program.

There is also a growing bevy of research describing serious outcomes resulting from interactions between benzodiazepines and opioids, a topic the FDA intends to address. “Once a review of all available scientific information is completed, the FDA will take necessary actions to ensure prescribers and the public are informed of the risks involved with the use of these medications,” the FDA stated.

The work comes as part of a broad initiative set forth this year by the FDA to work towards combating the devastating effects of opioid abuse in the US, which also includes expanding access to naloxone, an opioid overdose antidote, and promoting the use of MAT, including opioid treatment programs (OTP), to help treat opioid use disorder.

"The broad set of actions announced today is reflective of the FDA's efforts to improve informed prescribing of opioids across the board," said Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, in the press release. "We have been and will continue to evaluate all new data to ensure that labels of opioid drugs contain appropriate prescribing information about the benefits and risks of prescription opioids."

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